PROJECT SUMMARY: An HIV-associated state of chronic inflammation persists despite antiretroviral therapy (ART) and is termed ?inflammaging?. Such inflammation is a significant contributor to the increased risk HIV+ individuals? experience of age- and HIV-associated co-morbidities. However, the physiological processes underlying it remain poorly understood. We have been investigating whether glycomic alterations in circulating glycoproteins play a role in the pathogenesis of inflammation in HIV+ individuals. Glycan alterations, in particular, loss of sialic acid (hypo-sialylation), on circulating glycoproteins are known to mediate inflammation and associate with biological age. In a recent publication, we found that levels of circulating, anti-inflammatory sialylated glycoproteins and immunoglobulins G (IgGs) are markedly reduced in the plasma of HIV+ individuals (viremic and ART-suppressed) compared to HIV- controls. This was intriguing because sialylated glycoproteins are known to initiate an anti-inflammatory response, possibly by inhibiting TLR4 signaling. Testing for a connection with co-morbidities, we found that levels of hypo-sialylation significantly correlate with the prevalence of several inflammation-associated co-morbidities in HIV+ ART+ individuals. These data support our hypothesis that HIV infection accelerates the pace of age-associated hypo-sialyation, which contributes to inflammaging. Consistent with the work of others suggesting that hypo-sialyation not only correlates with inflammation, but also mechanistically drive it, we showed that sialic-acid coated nanoparticles reduce immune activation/inflammation in the physiologically-relevant BLT humanized mouse model of HIV infection. We posit that normalizing glycosylation patterns will prevent the development of HIV-associated inflammation. In Aim 1 we will test the hypothesis that age-associated hypo-sialylation of circulating glycoproteins and IgGs is accelerated in HIV+ individuals compared to HIV- counterparts and is linked to inflammaging. We will use advanced glycomic technologies and well-powered, cross-sectional, and longitudinal plasma samples from well- characterized cohorts of HIV (WIHS and MACS), to establish a longitudinal relationship between glycomic profiles, aging with HIV, inflammation, and the prevalence of subclinical atherosclerosis (as an example of inflammation-associated co-morbidity). We also will test the hypothesis that enhanced activity of sialidase underlies the hypo-sialyation observed in HIV+ ART+ individuals. In Aim 2, we will test the hypothesis that sialic acid coated nanoparticles can prevent immune activation/inflammation during ART-suppressed HIV infection, using HIV-infected, ART-suppressed BLT humanized mice. We will also test if these effects are mediated by inhibiting TLR4 signaling. We are taking advantage of recent advances in the emerging field of glycomics to clarify the association between HIV, aging, and the host immune environment during ART. We aim to create a new paradigm for discovering novel glycomic-based biomarkers of aging with HIV and novel glycan-based interventions to prevent inflammation and the development of aging-related conditions in HIV+ individuals.